N-Acylethanolamine-hydrolyzing acid amidase (NAAA) is a lysosomal enzyme, which plays a central role in the deactivation of N-palmitoylethanolamine (PEA) (Chemistry & Biodiversity. 2007; 4: 1914-25). PEA is an endogenous lipid produced on-demand by most mammalian cells (The Journal of biological chemistry. 2004; 279: 5298-305). A growing body of evidence links PEA in the regulation of inflammatory and pain processes. PEA reduces peripheral inflammation (Eur. J Pharmacol. 1996; 300: 227-36; Neuropharmacology. 2005; 48: 1154-63; Gut. 2013) and exerts neuroprotective (Epilepsia 2001; 42: 321-7) and antinociceptive effects (Nature. 1998; 394: 277-81) in rats and mice. Local and systemic administration of PEA alleviated pain behaviors elicited by chemical irritants and was effective even when administered after induction (Pain 1998; 76: 189-99) of acute inflammation (Br. J. Pharmacol. 2002; 137: 413-20). The PEA levels in ulcerative colitis patients were assessed by biopsy of the mast cells (Am. J. Gastroenterol. 2002; 97: 3071-7; Inflamm. Bowel Dis. 2003; 9: 224-9). Mast cells produce high amounts of PEA (The Journal of Biological Chemistry. 1997; 272: 3315-23) that potently inhibit mouse small intestine motility and visceral pain in mice (Br. J. Pharmacol. 2001; 134: 945-50). Thus, the presence of elevated levels of PEA in colonic biopsies strengthens the hypothesis that this compound participates in the control of visceral pain and intestinal motility.
PEA is an endogenous agonist for the peroxisome proliferator-activated receptor-α (PPARα) (Nature. 2003; 425: 90-3; Life Sci. 2005; 77: 1685-98), which is expressed in the intestinal mucosa of the small intestine and colon. Activation of PPARα with endogenous or exogenous ligands resulted in the amelioration of di-nitrobenzene sulfonic acid (DNBS)-induced colitis, suggestive of the potential role of PPARα ligands as novel therapies for GI inflammatory conditions (The Journal of Investigative Dermatology. 2002; 118: 94-101; Laboratory Investigation; a journal of Technical Methods and Pathology. 2004; 84: 1643-54). However, the prolonged clinical use of exogenous PPARα ligands was linked to a variety of severe side-effects, including oncogenesis, renal dysfunction, rhabdomyolysis, and cardiovascular toxicity (JAMA. 2007; 297: 1362-73), therefore, modulation of PPARα activity with endogenous ligands such as PEA may provide a safer treatment. Pharmacologic strategies aimed at correcting a deficit in PEA/PPARα signaling by preventing PEA degradation provide a new mechanism for the treatment of inflammatory disorders. NAAA inhibition offers the advantage of blocking PEA degradation under inflammatory stress and stimulating PPARα activation. A reduction in the reinforcing addictive nature for drugs of abuse has also been reported for inhibition of NAAA (Addict Biol. 2010; 15(3):277-88). These characteristics make NAAA an excellent therapeutic target for discovery of novel compounds to treat pain and inflammation without the addictive properties of opioids.